Antibodies In Myasthenia Gravis Research Articles

Elevated C1s/C1-INH in serum and plasma of myasthenia gravis patients

Myasthenia Gravis (MG) is an autoimmune neuromuscular disorder where acetylcholine receptor (AChR) antibodies induce membrane attack complex formation at the muscle membrane. The C1-inhibitor (C1-INH) regulates the classical pathway and is a promising marker in other autoimmune disorders. Treatment options for AChR antibody MG include complement inhibitors; nevertheless, the early pathway activation in MG remains unclear. Serum and plasma C1s-C1-INH levels were higher in MG patients than in matched healthy controls, supporting early classical pathway activation in most MG patients. These findings allow prospective validation studies of activated C1s as a putative treatment target and potential accompanying biomarker in MG.

Genetic analysis of a family affected by congenital myasthenic syndrome due to a Novel mutation in the SLC5A7 gene

BackgroundMutations in the SLC5A7 gene cause congenital myasthenia, a rare genetic disorder. Mutation points in the SLC5A7 gene differ among individuals and encompass various genetic variations; however, exon deletion variants have yet to be reported in related cases. This study aims to explore the clinical phenotype and genetic traits of a patient with congenital myasthenic syndrome due to SLC5A7 gene variation and those of their family members.Case presentationWe describe a case of a Chinese male with congenital myasthenic syndrome presenting fluctuating limb weakness. Genetic testing revealed a heterozygous deletion mutation spanning exons 1–9 in the SLC5A7 gene. QPCR confirmed a deletion in exon 9 of the SLC5A7 gene in the patient’s mother and brother. Clinical symptoms of myasthenia improved following treatment with pyridostigmine.ConclusionExons 1, 5, and 9 of the SLC5A7 gene encode the choline transporter’s transmembrane region. Mutations in these exons can impact the stability and plasma membrane levels of the choline transporter. Thus, a heterozygous deletion in exons 1–9 of the SLC5A7 gene could be the pathogenic cause for this patient. In patients exhibiting fluctuating weakness, positive RNS, and seronegativity for myasthenia gravis antibodies, a detailed family history should be considered, and enhanced genetic testing is recommended to determine the cause.

Functional Signature of LRP4 Antibodies in Myasthenia Gravis.

Antibodies (Abs) specific for the low-density lipoprotein receptor-related protein 4 (LRP4) occur in up to 5% of patients with myasthenia gravis (MG). The objective of this study was to profile LRP4-Ab effector actions. We evaluated the efficacy of LRP4-specific compared with AChR-specific IgG to induce Ab-dependent cellular phagocytosis (ADCP), Ab-dependent cellular cytotoxicity (ADCC), and Ab-dependent complement deposition (ADCD). Functional features were additionally assessed in an independent AChR-Ab+ MG cohort. Levels of circulating activated complement proteins and frequency of Fc glycovariants were quantified and compared with demographically matched 19 healthy controls. Effector actions that required binding of Fc domains to cellular FcRs such as ADCC and ADCP were detectable for both LRP4-specific and AChR-specific Abs. In contrast to AChR-Abs, LRP4-binding Abs showed poor efficacy in inducing complement deposition. Levels of circulating activated complement proteins were not substantially increased in LRP4-Ab-positive MG. Frequency of IgG glycovariants carrying 2 sialic acid residues, indicative for anti-inflammatory IgG activity, was decreased in patients with LRP4-Ab-positive MG. LRP4-Abs are more effective in inducing cellular FcR-mediated effector mechanisms than Ab-dependent complement activation. Their functional signature is different from AChR-specific Abs.

FRI564 Thymic Hyperplasia In Graves' Disease: An Under-recognized Association

Abstract Disclosure: S. Nachum: None. A. Rivadeneira: None. K.N. Kobaly: None. Association of thymic hyperplasia (TH) with Graves’ disease (GD) is rare and underrecognized. In an era of increased diagnostic imaging, incidental findings of thymic masses in patients with GD may be increasingly identified and awareness of this association may reduce unnecessary interventions. We report three cases of GD with TH at presentation, one of which includes resolution of TH. CASE 1: 56 year-old man with unintentional weight loss, palpitations and eye discomfort was diagnosed with GD (TSH <0.015, FT4 4.47, TRAB 8.18, TSI 8.51). He had an incidental 3x3 cm anterior mediastinal mass on a chest CT. MRI chest suggested TH. Myasthenia gravis antibodies were negative. I-123 uptake and scan showed diffusely increased uptake within the thyroid gland and no increased uptake in the upper chest corresponding to mediastinal mass. Initiation of methimazole normalized thyroid function. CT chest at 9 months showed near resolution of the anterior mediastinal soft tissue density compatible with resolving TH. CASE 2: 23 year-old woman presented with insomnia, palpitations, and neck pain and was found to have GD (TSH <0.01, FT4 2.75, TRAB 9.16, TSI 8.84). CT neck obtained due to pain showed diffuse enlargement of the thyroid and a soft tissue density in the partially imaged superior mediastinum. Methimazole was started. Further evaluation of mass is pending. CASE 3: 35 year-old man presented with atrial fibrillation and was diagnosed with hyperthyroidism (TSH < 0.01, FT4 5.55). Tc-99m pertechnetate scan showed diffuse uptake consistent with GD. Methimazole was started. CT chest obtained due to concern for pulmonary embolism showed a 12.6 x 3.0 cm anterior mediastinal mass. HCG was undetectable. Further evaluation of mass is pending. Discussion: TH is thought to occur due to hormonal excess stimulating the thymic cortex and immunological mechanisms that result in formation of medullary lymphoid follicles.1 The incidence of TH in GD is unknown as diagnostic imaging is not routinely obtained. A study of thymic biopsies in patients undergoing thyroidectomy found 38% of patients with thyrotoxicosis had histological evidence of TH.2 This benign condition improves with treatment of GD, with decreased thymic size after 5-24 months of treatment with antithyroid drugs.3 In the absence of a discrete mass, invasion of other tissues or calcifications, repeat imaging after 6 months with regression of TH by 50% obviates the need for biopsy.1 Biopsy and thymectomy should be deferred when thyrotoxic due to risk of precipitating thyroid storm4 and be reconsidered if thymus fails to regress on repeat imaging. Additional guidance for observation is needed as the differential diagnosis for mediastinal mass includes diseases warranting more urgent diagnosis and intervention. Identification of high-risk patient characteristics or imaging findings may be of clinical utility in this circumstance. Presentation: Friday, June 16, 2023

Clinical Analysis of 2 Cases of Late-onset Myasthenia Gravis

Objective: Improve the recognition ability of late-onset myasthenia gravis, reduce misdiagnosis and improve prognosis. Methods: The data of 2 patients with late-onset myasthenia gravis were collected, including basic information, clinical features, auxiliary examinations, treatment and effects. Results:: Both male patients were elderly. The clinical manifestations were bulbar palsy with diplopia or limb weakness. Symptoms were mild in the morning and severe in the evening, and the neostigmine test was positive. According to the criteria, myasthenia gravis was diagnosed, and pyridostigmine treatment was effective. The severity of the condition was different. Tests for myasthenia gravis antibodies, thyroid function, autoimmune antibodies, and tumor markers were also different. Follow-up of treatment effect was required for prognosis. Conclusion: Late-onset myasthenia gravis is easily misdiagnosed. Neurological examination can help to detect skeletal muscle involvement, and medical history can help to detect clinical features. The auxiliary examinations of myasthenia gravis have clinical significance for the diagnosis, treatment and prognosis.

Immunological and Structural Characterization of Titin Main Immunogenic Region; I110 Domain Is the Target of Titin Antibodies in Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies targeting the neuromuscular junction (NJ) of skeletal muscles. The major MG autoantigen is nicotinic acetylcholine receptor. Other autoantigens at the NJ include MuSK, LRP4 and agrin. Autoantibodies to the intra-sarcomeric striated muscle-specific gigantic protein titin, although not directed to the NJ, are invaluable biomarkers for thymoma and MG disease severity. Thymus and thymoma are critical in MG mechanisms and management. Titin autoantibodies bind to a 30 KDa titin segment, the main immunogenic region (MIR), consisting of an Ig-FnIII-FnIII 3-domain tandem, termed I109-I111. In this work, we further resolved the localization of titin epitope(s) to facilitate the development of more specific anti-titin diagnostics. For this, we expressed protein samples corresponding to 8 MIR and non-MIR titin fragments and tested 77 anti-titin sera for antibody binding using ELISA, competition experiments and Western blots. All anti-MIR antibodies were bound exclusively to the central MIR domain, I110, and to its containing titin segments. Most antibodies were bound also to SDS-denatured I110 on Western blots, suggesting that their epitope(s) are non-conformational. No significant difference was observed between thymoma and non-thymoma patients or between early- and late-onset MG. In addition, atomic 3D-structures of the MIR and its subcomponents were elucidated using X-ray crystallography. These immunological and structural data will allow further studies into the atomic determinants underlying titin-based autoimmunity, improved diagnostics and how to eventually treat titin autoimmunity associated co-morbidities.

A single low-dose rituximab infusion in severe chronic refractory myasthenia gravis in resource-limited settings

The benefits of multi-dose rituximab cycles in patients with refractory anti-muscle-specific kinase antibody myasthenia gravis (MuSK+MG) are well reported, although less consistently in anti-acetylcholine receptor antibody MG (AChR+MG). Responsivity data to single low-dose rituximab infusions for refractory autoimmune myasthenia, are limited. Here, observational outcomes using MG grading scores and prednisone doses, before and after at least six months of a single-dose infusion of rituximab, were audited in previously treatment-refractory MG patients in a resource-limited setting. Seventeen moderately-severe to severely symptomatic MG patients received single low-dose rituximab infusions (median 500-600 mg) after a median MG duration of 6 years; 13 individuals responded including 5/5 MuSK+MG, 7/10 AChR+MG and 1/2 double seronegative MG. Three (60%) MuSK+MG and three (30%) AChR+MG achieved persistent asymptomatic status. Although more MuSK+MG vs AChR+MG cases stopped prednisone (80% vs 20%, respectively), the prednisone doses in the AChR+MG group was significantly reduced ≥30% (p = 0.008) due to improved MG composite scores (p = 0.016) and with durable benefit (median 12 months). There were no differences between responders and non-responders in MG duration and age at infusion. These results suggest that a single low-dose rituximab infusion is worth trying in refractory MG, including AChR+MG patients, as some patients showed good and durable responses. These results are particularly relevant to resource-limited settings.

Post-malaria Myasthenia Gravis

We report a nine-year-old girl who presented with complete drooping of the left eyelid and restriction ofmedial gaze following an attack of febrile illness. The child was admitted into a rural hospital where shewas misdiagnosed and managed as a case of meningitis. She was referred to a tertiary children hospitalwhen her condition was not improving and where she developed the eye signs. She was diagnosed as a caseof severe malaria which responded well to quinine therapy. In our neurophysiology clinic, examinationrevealed partial unilateral left eye ptosis, weak frontalis, neck flexors, fingers extensors & knee flexors.Her investigations revealed positive neostigmine test, decremental response to repetitive nerve stimulation(-15.6%,nasalis), increased jitter in single-fibre electromyography (left frontalis & extensor-digitorumcommunis) and negative serology for myasthenia gravis antibodies. She showed remarkable improvementafter pyridostigmine therapy which continued for three months. Regular follow-up showed no recurrenceof her symptoms.

DON’T JUDGE A BOOK BY ITS COVER: UNUSUAL CASE OF MYASTHENIA GRAVIS

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Myasthenia gravis is an autoimmune disorder where auto-antibodies bind to the acetylcholine receptors present in the post-synaptic membrane of the neuromuscular junction. It typically presents with limb weakness but may also include ocular symptoms such as diplopia and ptosis or bulbar symptoms including dysphagia, dysphonia and dysarthria. We report an atypical case of myasthenia gravis that initially appeared to be consistent with the diagnosis of asthma. CASE PRESENTATION: The patient is a 78-year old female with a past medical history of remote deep venous thrombosis associated with pulmonary embolism, hypertension, rheumatoid arthritis, and polymyalgia rheumatica who was referred to pulmonology for eight months of exertional dyspnea and fatigue. Besides her progressive dyspnea, additional respiratory symptoms included chest tightness, non-productive cough, and wheezing. Her pulmonary function tests indicated a mixed obstructive and restrictive defect with FEV1/FVC ratio of 69% with FVC of 1.63L (62 % predicted) as well as a positive bronchodilatory response. She was started on a regimen of ICS/LABA, leukotriene inhibitor, and an as needed ß2-recptor agonist for presumed late-onset asthma in which her symptoms only partially improved. Given both the severity of her dyspnea and restrictive physiology on her pulmonary function testing in absence of parenchymal lung disease, the patient underwent additional neuromuscular evaluation. Her maximal inspiratory pressure (MIP) was 15% predicted and her maximal expiratory pressure (MEP) was 16% predicted in setting of a normal diaphragmatic fluoroscopy (SNIFF test). She subsequently underwent serological evaluation for neuromuscular weakness in which her acetylcholine binding antibody was positive, confirming the diagnosis of myasthenia gravis. The patient was started on acetylcholinesterase inhibitor and steroids with a mixed response. Due to progression of her illness, she eventually required ICU admission and was started on plasmapheresis with positive clinical response. DISCUSSION: Acetylcholine receptor antibody myasthenia gravis has a bimodal pattern with early onset prior to age of 50. It uncommonly can be seen in setting of other autoimmune disorders such as systemic lupus, thyroiditis, or as seen in our patient, rheumatoid arthritis. Our case is unique given the fact that patient initially presented with clinical features suggestive of late-onset asthma. However, given only partial improvement in symptoms and unexplained restrictive physiology on spirometry, further testing revealed diagnosis of myasthenia gravis. CONCLUSIONS: This case stresses the need for thorough evaluation for all patients with unexplained progressive dyspnea. Reference #1: Gilhus NE. Myasthenia Gravis. Longo DL, ed. N Engl J Med. 2016;375(26):2570-2581. doi:10.1056/NEJMra1602678 Reference #2: Marlowe FI, D’Angelo AJ. Respiratory failure as the initial presentation of myasthenia gravis. Ear Nose Throat J. 1989;68(6):472-473. Reference #3: Qureshi AI, Choundry MA, Mohammad Y, et al. Respiratory failure as a first presentation of myasthenia gravis. Med Sci Monit. 2004;10(12):CR684-689. DISCLOSURES: No relevant relationships by Shubham Adroja, source=Web Response No relevant relationships by Anthony Cucci, source=Admin input No relevant relationships by Urbee Haque, source=Web Response

SAT-108 Growth Hormone Deficiency in a Patient with Ectodermal Dysplasia

Background information:Ectodermal dysplasia (ED) is a rare heterogeneous group of genetic disorders of ectodermal derived tissues, characterized by abnormalities in skin, teeth, hair and eccrine glands. Growth failure in these children varies depending on the genetic mutation and has not been well characterized. This clinical case report presents a 11-year-old male with a heterozygous mutation in WNT 10 A, a variant of the hypohydrotic ED gene, who was found to have growth hormone (GH) deficiency and treated with GH.Case report:He was born at 35 weeks gestation by C-section with a birth weight of 5 lbs. 12 oz. to a mother who had invitro fertilization with donor eggs from the maternal aunt with ocular myasthenia gravis and sperm from the father. Pregnancy was complicated by twin gestation and polyhydraminos. He had transient myasthenia gravis and treated with pyridostigmine for 3 months for feeding problems and swallowing difficulty. He also had arthrogryposis of the distal upper extremities attributed to placental transfer of the maternal aunt’s myasthenia gravis antibodies.He was referred to the endocrine clinic for evaluation of his growth failure around the age of 8 years. His growth chart indicated that he grew along the 5thpercentile until age 5 year with a gradual decline to the 3rd percentile by age 7 year and close to 2nd percentile by age 8 year. His BMI was at 7th percentile. Mid parental height was 5’9”. There was no history of delayed adolescence in the family. His twin sister had very mild form of arthrogryposis with dental delay but steady linear growth. He also had decreased exercise tolerance. His body tended to become hot during sports activities and had to wrap his face and neck with cold soaked towels. His other problems included delayed dental development with conical incisor, thin nail, missing teeth and hearing defects that raised suspicion for ectodermal dysplasia. Genetic testing at the age of 4 years had demonstrated a heterozygous mutation in the WNT 10A gene, an important gene for tooth development. Physical examination revealed a mild facial dysmorphism with conical incisor, missing teeth and high arched palate. He had contracture of the proximal inter phalangeal joints of the hands. Investigations revealed a normal thyroid function test, IGF-1 and IGFBP-3 level, CBC, sedimentation rate, chemistry panel and celiac titer. The bone age was concordant with his chronological age of 8 years. A GH stimulation study demonstrated a peak GH level of 4.94 ng/ml. An MRI of the brain revealed a normal pituitary gland. He was started on GH therapy with 0.3 mg/kg/week at age 9 year. His height improved from 2nd percentile at age 9 year to 20th percentile by age 11 year on growth hormone therapy. His exercise capacity and stamina also improved.Conclusion:Growth failure and GH axis should be evaluated in children with ED. GH therapy improves growth velocity and exercise capacity in patients with ED.

Simultaneous Presence of Acetylcholine Receptor and Muscle Specific Tyrosine Kinase Antibodies in Myasthenia Gravis

Myasthenia gravis (MG) is known as an autoimmune disorder which affects transmission in neuromuscular junction. The serologic tests used for diagnosis include acetylcholine receptor and muscle specific receptor tyrosine kinase antibodies. Studies often have reported that patients with formal antibody are negative for the latter one. However, very limited studies have reported positive anti-muscle specific receptor tyrosine kinase antibody in a small percentage of patients with acetylcholine receptor antibody. Here, we reported a young woman who was diagnosed with MG and had a rapid and progressive course of the disease. She was seropositive for both acetylcholine receptor and muscle-specific receptor tyrosine kinase antibodies simultaneously. However, she discharged from the hospital with good condition after treatment.

Anti-musk antibody myasthenia gravis: Clinical findings and long term follow up

Myasthenia gravis (MG) is adisorder neuro-muscular junction where 50-85% patients have acetylcholine receptor antibody (AChR-Ab). About 30-40% sero-negative patients have antibodies to muscle-specific tyrosine kinase (MuSK). This disorder represents a distinct subset of MG where clinical features and treatment options are different. We retrospectively analysed MuSK-MG patients seen at our center in last 4 years. From 2015 to 2019, there were 6 MuSK-MG patients. Eighty-three percent were female, with disease onset in the fourth to fifth decade. Oculobulbar symptoms were present at onset in 83%. Eventually ocular involvement was seen in 83%, bulbar in 83% and limbs weakness in 83%. Fifty percent patients had myasthenic crisis. No patient had antibodies to AchR and of those tested, CT scan of thorax did not show any thymic tumour. No patients responded to pyridostigmine. Sixty six percent patients had moderate to good response to steroids. Sixty six percent patients were treated with plasma exchange (PLEX) which produced improvement while none was treated with intravenous immunoglobulin. Immunosupression with azathioprine (50%), mycophenolate (16%) and rituximab (50%) was used during the course of illness. All patients achieved good remission over a median follow up of 2 years. MuSK-MG has a marked female predominance with frequent oculobulbar weakness and crises. Pyridostigmine does not help to relieve symptoms and PLEx shows better results compared to steroids. Most patients need immunosuppression and remission can be achieved with it.

Do Myelin Oligodendrocyte Glycoprotein Antibodies Represent a Distinct Syndrome?

Do Myelin Oligodendrocyte Glycoprotein Antibodies Represent a Distinct Syndrome?

Cytometric cell-based assays for anti-striational antibodies in myasthenia gravis with myositis and/or myocarditis

The purposes of the present study were to identify anti-striational antibodies in myasthenia gravis (MG) patients with myositis and/or myocarditis using a combination of cell-based assays and flow cytometry (cytometric cell-based assays) and to describe the main clinical implications. Among 2,609 stored samples collected from all over Japan between 2003 and 2016, we had serum samples from 30 MG patients with myositis and/or myocarditis. Cytometric cell-based assays with titin, ryanodine receptor, and voltage-gated Kv1.4 were performed. Autoantibodies were determined by differences in phycoerythin fluorescence between the 293F cells and titin-transfected cells. MG patients with myositis and/or myocarditis as well as late-onset and thymoma-associated MG had anti-titin, anti-ryanodine receptor, and anti-Kv1.4 antibodies. In contrast, patients with early-onset MG, those with other myopathies and healthy controls did not have anti-titin or anti-Kv1.4 antibodies with some exceptions, but they possessed anti-ryanodine receptor antibodies. Thirty MG patients with myositis and/or myocarditis showed a severe generalized form, and 21 of them had thymoma. Anti-titin and anti-Kv1.4 antibodies were found in 28 (93%) and 15 (50%) patients, respectively, and all patients had at least one of these antibodies. Cytometric cell-based assays thus demonstrated that anti-striational antibodies are biomarkers of MG with myositis and/or myocarditis.

Present validity of “maximal” thymectomy in the treatment of myasthenia gravis

The role of the thymus in the development and pathogenesis of acetylcholine antibody myasthenia gravis is well documented. The ability of thymectomy to alter the course of the disease has been debated for many years, and now finally has been proven to clearly improve patients with the publication of the prospective randomized trial of thymectomy versus medical therapy alone. The trial definitively proves the validity of thymectomy for non-thymomatous myasthenia gravis, the maximal thymectomy surgical resection tested in the trial was critically chosen to address the anatomic presence of thymic tissue outside of the confines of the defined lobes of the thymus in the neck and mediastinum. Given the clear results of the trail, presently maximal thymectomy is the only proven valid resection in the treatment of myasthenia gravis.

Diagnostic utility of cortactin antibodies in myasthenia gravis.

Patients with myasthenia gravis (MG) without antibodies to the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) have been classified as having double-seronegative myasthenia gravis (dSNMG). We used the sera from six dSNMG patients with positive immunohistochemistry assays in a protein array to screen reactivity with 9000 human proteins. We identified cortactin, an intracellular protein that interacts with agrin/MuSK favoring AChR aggregation, as a new antigen in dSNMG. We then designed an in-house enzyme-linked immunosorbent assay as a screening assay and confirmed these results by western blot. We found that 19.7% of dSNMG patients had anti-cortactin antibodies. In contrast, patients with AChR+ MG or other autoimmune disorders and healthy controls were positive at significantly lower rates. Five percent of healthy controls were positive. In a recent study, we screened sera from 250 patients (AChR+ MG, MuSK+ MG, dSNMG) and 29 healthy controls. Cortactin antibodies were identified in 23.7% of dSNMG and 9.5% AChR+ MG patients (P = 0.02). None of the MuSK+ MG patients, patients with other autoimmune disorders, or healthy controls had antibodies against cortactin. Patients with dSNMG cortactin+ MG were negative for anti-striated muscle and anti-LRP4 antibodies. Patients with dSNMG cortactin+ MG presented ocular or mild generalized MG without bulbar symptoms. We conclude that cortactin autoantibodies are biomarkers of MG that, when present, suggest that the disease will be mild.

Giant Thymoma and Cardiac Tamponade

SESSION TITLE: Student/Resident Case Report Poster - Cardiac and Thoracic Surgery SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: The thymus is a gland overlying the pericardium and great vessels in the anterior mediastinum that typically involutes after puberty. Thymomas are rare tumors of the thymus gland in which associated pericardial effusions are found in a minority while hemorrhagic pericardial effusion causing tamponade physiology is extremely rare (1). We present a case of a patient who had hemorrhagic pericardial effusion with cardiac tamponade due to a malignant Type B2 Thymoma. CASE PRESENTATION: A 51-year-old previously healthy male presented to the hospital with a four-week history of progressive dyspnea on exertion, orthopnea, and pleuritic chest pain, as well as, six months of 40-pound weight loss. On examination, he was found to be tachycardic with normal heart sounds, distended neck veins, and bilateral basal lung rales. Pulsus paradoxus was 24 mm Hg. Electrocardiogram showed sinus arrhythmia with tachycardia, diffuse low voltage QRS complexes and T-wave flattening in the inferior leads, without electrical alternans. His CBC showed leukocytosis with lymphocytic predominance. Other labs, including ESR, CRP, TSH, ANA, HIV, Rheumatoid Factor, syphilis and myasthenia gravis antibodies, were within normal limits. A Chest X-ray demonstrated an enlarged Cardiac silhouette and a large anterior mediastinal mass. Transthoracic echocardiogram showed a large pericardial effusion with tamponade physiology, as well as, a mass anterior to the right heart. An urgent pericardiocentesis was performed draining 640 ml of bloody fluid with the resolution of tamponade. Chest CT confirmed a large anterior mediastinal mass (16.3 x 19.5 x 20.6 cm) with central areas of necrosis and significant mass effect on the heart, trachea, and the bilateral main stem bronchi. Subsequently, the patient underwent mediastinoscopy with biopsy and flow cytometry demonstrating malignant Type B2 Thymoma. The patient was treated with neoadjuvant chemotherapy with cisplatin, doxorubicin, cyclophosphamide, and prednisone. He then underwent surgical debulking with plans for radiation therapy. DISCUSSION: The overall incidence of thymoma is 0.15 cases per 100,000 (2). Hemorrhagic pericardial effusion with cardiac tamponade represents a rare initial presentation of Malignant Thymoma. CONCLUSIONS: Thymic pathologies should be included as a rare etiology in the differential diagnosis of hemorrhagic pericardial effusion and cardiac tamponade. To the best of our knowledge, this case represents the largest malignant thymoma that has been diagnosed with a presentation of hemorrhagic pericardial effusion and cardiac tamponade Reference #1: Takanami I, Takeuchi K, Naruke M. Noninvasive large thymoma with a natural history of twenty-one years. J Thorac Cardiovasc Surg. 1999;118:1134-1135. doi: 10.1016/S0022-5223(99)70120-0. Reference #2: Engels EA, Pfeiffer RM: Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 105(4):546-51, 2003 DISCLOSURE: The following authors have nothing to disclose: Irfan Ahsan, Wisam Alfay, Jenna Jarriel, Gregary Marhefka No Product/Research Disclosure Information

Unusual association of amyotrophic lateral sclerosis and myasthenia gravis: A dysregulation of the adaptive immune system?

Myasthenia gravis is an autoimmune disorder affecting neuromuscular junctions that has been associated with a small increased risk of amyotrophic lateral sclerosis (ALS). Here, we describe a retrospective series of seven cases with a concomitant diagnosis of ALS and myasthenia gravis, collected among the 18 French reference centers for ALS in a twelve year period. After careful review, only six patients strictly met the diagnostic criteria for both ALS and myasthenia gravis. In these patients, limb onset of ALS was reported in five (83%) cases. Localization of myasthenia gravis initial symptoms was ocular in three (50%) cases, generalized in two (33%) and bulbar in one (17%). Median delay between onset of the two conditions was 19 months (6–319 months). Anti-acetylcholine receptor antibodies testing was positive in all cases. All patients were treated with riluzole and one had an associated immune-mediated disease. In the one last ALS case, the final diagnosis was false-positivity for anti-acetylcholine receptor antibodies. The co-occurrence of ALS and myasthenia gravis is rare and requires strict diagnostic criteria. Its demonstration needs thoughtful interpretation of electrophysiological results and exclusion of false positivity for myasthenia gravis antibody testing in some ALS cases. This association may be triggered by a dysfunction of adaptive immunity.

Characterization of B cells in muscle-specific kinase antibody myasthenia gravis.

Objective:To characterize B-cell subsets in patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG).Methods:In accordance with Human Immunology Project Consortium guidelines, we performed polychromatic flow cytometry and ELISA assays in peripheral blood samples from 18 patients with MuSK MG and 9 healthy controls. To complement a B-cell phenotype assay that evaluated maturational subsets, we measured B10 cell percentages, plasma B cell–activating factor (BAFF) levels, and MuSK antibody titers. Immunologic variables were compared with healthy controls and clinical outcome measures.Results:As expected, patients treated with rituximab had high percentages of transitional B cells and plasmablasts and thus were excluded from subsequent analysis. The remaining patients with MuSK MG and controls had similar percentages of total B cells and naïve, memory, isotype-switched, plasmablast, and transitional B-cell subsets. However, patients with MuSK MG had higher BAFF levels and lower percentages of B10 cells. In addition, we observed an increase in MuSK antibody levels with more severe disease.Conclusions:We found prominent B-cell pathology in the distinct form of MG with MuSK autoantibodies. Increased BAFF levels have been described in other autoimmune diseases, including acetylcholine receptor antibody–positive MG. This finding suggests a role for BAFF in the survival of B cells in MuSK MG, which has important therapeutic implications. B10 cells, a recently described rare regulatory B-cell subset that potently blocks Th1 and Th17 responses, were reduced, which suggests a potential mechanism for the breakdown in immune tolerance in patients with MuSK MG.

Detection of Acetylcholine Receptor Modulating Antibodies by Flow Cytometry

To determine the clinical utility and performance characteristics of a laboratory-adapted flow cytometric method for the detection of acetylcholine receptor (AChR) modulating antibodies in myasthenia gravis (MG). Serum samples from 120 healthy donors and 100 patients with suspected MG were assessed for the ability to reduce surface AChR concentrations (antigenic modulation) in RD (TE671) or DB40 human muscle cell lines by flow cytometry. Reference ranges were established by receiver operating characteristic curve analysis, and results were then compared with those of the current radioimmunoassay (RIA). Flow cytometric results from the RD cell line had an interpretive threshold of 46% modulation or greater and correlated best (98% sensitivity, 99% specificity) with those of the current RIA. The new flow cytometric method using the RD cell platform provided higher quality clinical results, a more robust and efficient assay format, a significant cost savings, and less environmental burden.